Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV

Drug regimens containing integrase strand transfer inhibitors (INSTIs) are widely recommended by international guidelines for ART-naive people living with HIV (PLWH). 1,2 However, INSTI resistance mutations are uncommon and therefore their surveillance is not suggested before starting ART. The aim of the study was to evaluate the prevalence trend of transmitted INSTI drug resistance (DR) and to assess factors associated with transmitted INSTI resistance among ART-naive PLWH over the past decade. We conducted a time-trend, single-centre study over the period 2009 – 19 on adult naive PLWH with a genotypic resistance test (GRT) performed before the ART initiation. GRT was determined by Sanger sequencing using an ABI PRISM 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA); we included in the analysis the immediate pre-ART GRT available in people newly diagnosed with HIV infection. The degree of resistance to each INSTI drug was calculated using the Genotypic Resistance Interpretation Algorithm of the Stanford HIV Drug Resistance Database Program (version 9.1.1) (https://hivdb.stanford.edu/hivdb/by-patterns/). The obtained scores were used to classify the presence of low-level

A multivariable logistic regression model was fitted to determine factors associated with at least low-level transmitted INSTI DR; given the limited number of PLWH with transmitted INSTI DR. Three variables were included into the model: age; CD4 cell count at GRT; and HIV-1 subtype.
All the statistical tests were two-sided at 5% level and were performed using the SAS Software (release 9.4; SAS Institute, Cary, NC, USA).
At least low-level and at least intermediate INSTI DR were reported in 18 (1.5%) and 6 (0.5%), respectively.
Prevalence of at least low-level INSTI DR was anecdotal between 2009 and 2013 and then gradually raised from 1.3% in 2014 to 3.9% in 2019 (P for trend < 0.001) prevalence of at least intermediate INSTI DR increased from 0% in 2009 to 2% in 2019 (P for trend = 0.188). A significant increase over time in at least low-level DR prevalence has emerged to raltegravir and elvitegravir, not to dolutegravir and bictegravir (P for trend < 0.001), as shown in Figure 1(a and b).
Over the decade 2009-19, the prevalence of at least low-level and intermediate INSTI DR among ART-naive PLWH with an available GRT performed before starting ART has mildly increased, together with the proportion of non-B subtype infections; nonetheless, major INSTI-resistance mutations were very uncommon.

© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
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INSTI polymorphisms that may decrease susceptibility to INSTIs are not infrequent; 3 for instance, mutations like G163R/K are polymorphic in subtype F viruses but can also be nonpolymorphic when considering other HIV-1 subtypes; 4 however, if alone, they have little impact on INSTI activity. [5][6][7] For this reason, HIV-1 subtype non-B has proved to be the only factor associated with INSTI resistance.
Current guidelines do not recommend INSTI resistance testing in naive PLWH, with the exception of a suspected exposure to INSTI-resistant strains. 8 However, we have shown that firstgeneration INSTIs have a lower genetic barrier to resistance that could justify INSTI GRT implementation together with the evidence of the large use of INSTI regimens in ART-naive PLWH.
However, the small number of people with INSTI resistance mutations is a clear study limitation with an impact on the statistical power to detect significant effects.
In conclusion, the prevalence of at least low-level transmitted HIV-1 resistance to INSTIs is rare but has increased in recent years, mainly related to the first-generation INSTIs. Surveillance should still continue to monitor for future trends.